Developing new and efficient asymmetric conjugate addition reactions for carbon-carbon bond formation is a challenging area of organic synthesis. Some recent work has focused on organocatalytic Michael addition of carbonyl compounds to nitroalkenes. Among these reactions, Michael addition of aldehydes to nitroalkenes is of particular interest because of the valuable synthetic intermediates that are generated. β-Aryl nitroalkenes have been the most common Michael acceptors. These Michael reactions provide, for example, α,β-disubstituted-γ-nitrobutyl aldehydes. Access to adducts that bear only a single substituent adjacent to a carbonyl is of interest because such adducts can be readily converted to γ2-amino acids. γ2-Amino acids are important building blocks for γ-peptide and heterogeneous backbone foldamers.
Oligomers constructed from β-amino acid residues (“β-peptides”) or from combinations of α- and β-amino acid residues (“α/β-peptides”) can adopt protein-like folding patterns. The conformational properties of these oligomers provide a basis for ongoing development of β- and α/β-peptides that display interesting functional properties. β-Amino acid residues can be endowed with higher intrinsic folding propensities than those of α residues by installation of cyclic constraints to limit backbone torsional mobility. This capacity for residue-based rigidification has proven to be important for both structure and function of β- and α/β-peptide foldamers. Analogous benefits might result from the use of constrained γ-amino acid residues in foldamers, however it is difficult to explore the use of constrained γ-amino acid residues in foldamers because only a few types of ring-containing γ-amino acids are known. The few cyclic γ residues examined to date have been found to promote sheet secondary structure, which contrasts with the helix-favoring effects of the most common cyclic β-residues.
Additionally, the challenges of preparing enantiomerically pure γ-amino acids has limited the study of γ-peptide foldamers to date. Some routes to enantioenriched γ2-amino acids have been described but they typically involve specialized chiral auxiliaries. Chiral auxiliary routes are undesirable for preparing multigram quantities of protected γ2-amino acids bearing the diverse side chain functionality necessary for foldamer research.
Accordingly, new methods for the synthesis of γ2-amino acids would significantly aid the preparation and study of γ-peptide and heterogeneous backbone foldamers. Ring-containing γ-amino acids are also needed to further the study of peptide foldamers. New synthetic methods for the preparation of versatile adducts that can be converted to γ2-amino acids, and new methods for the preparation of cyclically constrained γ-amino acid residues, would be of significant value to the research community.